Understanding leptin signaling is essential for understanding body weight regulation. We discovered that leptin regulates the activity of the AMP-activated protein kinase (AMPK), a "metabolic master switch" and a fuel sensor. The overall goal of the current proposal is to understand the role of the AMPK pathway in the hypothalamus in mediating leptin's effects on energy homeostasis. Our data recent show that leptin and other anorexigenic hormones and nutrients inhibit AMPK activity in specific hypothalamic nuclei and orexigenic peptides activate it. In Aim 1 we will investigate the role of hypothalamic AMPK in leptin's effect on food intake and energy balance and whether dysregulatibn of this pathway could be a mechanism for leptin resistance. We will determine whether failure to inhibit AMPK activity in response to leptjn contributes to the leptin resistance that is characteristic of diet-induced obesity. In Aim 2 we will determine how the hypothalamic AMPK pathway integrates with other leptin signaling pathways (STAT3 and PIS kinase) in regulating food intake and body weight. In Aim 3 we will determine the neuronal pathways mediating the effects of AMPK on food intake and energy homeostasis using immunohistochemistry and expression of dominant negative and constitutively active AMPK in specific neurons using transgenic approaches combined with aderio associated viral vectors. In Aim 4 we will determine whether the effect of leptin on AMPK activity in the paraventricular hypothalamus is direct or indirect through neurons in the arcuate nucleus. We will also determine whether altering AMPK activity only in the PVH is sufficient to alter food intake and energy homeostasis. These studies will provide critical insights into the signaling circuits that mediate hormonal and nutrient regulation of energy balance.